Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy.
Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy.
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粘菌素诱导的神经母细胞瘤 2a 细胞凋亡涉及活性氧的产生、线粒体功能障碍和自噬
DOI：
10.1007/s12035-015-9396-7
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发表时间：
2016-09
影响因子：
5.1
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Dai C;Tang S;Velkov T;Xiao X
神经毒性仍然是一种与粘菌素治疗相关的不良反应，特征不明确。本研究的目的是探讨粘菌素诱导神经毒性的机制，使用小鼠神经母细胞瘤2a（N2 a）细胞系。N2 a神经元细胞的粘菌素处理（0-200 μM）以剂量依赖性方式诱导凋亡性细胞死亡。多粘菌素诱导的神经毒性与活性氧（ROS）水平的显著增加相关，同时伴有超氧化物歧化酶（SOD）、过氧化氢酶（CAT）活性和谷胱甘肽（GSH）水平的降低。线粒体功能障碍是明显的，从膜电位的耗散和Bax/Bcl-2的增加，随后细胞色素c（CytC）的释放。还检测到半胱天冬酶-3/7、-8和-9活化。多粘菌素诱导的神经毒性显著增加了p53（1.6倍）、Bax（3.3倍）和caspase-8（2.2倍）的基因表达（allp< 0.01）。自噬空泡的形成是明显的，在粘菌素处理（50-200 μM）后Beclin 1和LC 3B两者均显著增加（a11 p < 0.05或0.01）。此外，自噬的抑制预处理与氯喹二磷酸（CQ）增强粘菌素诱导的细胞凋亡，通过半胱天冬酶激活，这可以减弱与泛半胱天冬酶抑制剂Z-VAD-FMK的共同治疗。总之，我们的研究表明，粘菌素诱导的神经元细胞死亡涉及ROS介导的氧化应激和线粒体功能障碍，其次是半胱天冬酶依赖的凋亡和自噬。粘菌素诱导的神经毒性中涉及的神经元信号传导途径的知识库将极大地促进与粘菌素组合使用以防止这种不期望的副作用的神经保护剂的发现。
Neurotoxicity remains a poorly characterized adverse effect associated with colistin therapy. The aim of the present study was to investigate the mechanism of colistin-induced neurotoxicity using the mouse neuroblastoma2a (N2a) cell line. Colistin treatment (0–200 μM) of N2a neuronal cells induced apoptotic cell death in a dose-dependent manner. Colistin-induced neurotoxicity was associated with a significant increase of reactive oxygen species (ROS) levels, with a concomitant decrease in the activities of superoxide dismutase (SOD), catalase (CAT), and the glutathione (GSH) levels. Mitochondrial dysfunction was evident from the dissipation of membrane potential and the increase of Bax/Bcl-2, followed by the release of cytochrome c (CytC). Caspase-3/7, -8, and -9 activations were also detected. Colistin-induced neurotoxicity significantly increased the gene expression of p53 (1.6-fold), Bax (3.3-fold), and caspase-8 (2.2-fold) (allp< 0.01). The formation of autophagic vacuoles was evident with the significant increases (allp< 0.05 or 0.01) of both of Beclin 1 and LC3B following colistin treatment (50–200 μM). Furthermore, inhibition of autophagy by pretreatment with chloroquine diphosphate (CQ) enhanced colistin-induced apoptosis via caspase activation, which could be attenuated by co-treatment with the pan-caspase inhibitor Z-VAD-FMK. In summary, our study reveals that colistin-induced neuronal cell death involves ROS-mediated oxidative stress and mitochondrial dysfunction, followed by caspase-dependent apoptosis and autophagy. A knowledge base of the neuronal signaling pathways involved in colistin-induced neurotoxicity will greatly facilitate the discovery of neuroprotective agents for use in combination with colistin to prevent this undesirable side effect.
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DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J
影响因子：
3.2
作者：
Dai, Chongshan;Li, Jichang;Li, Jian
通讯作者：
Li, Jian
关于粘菌素诱导小鼠中枢神经组织线粒体功能障碍的神经毒性的新见解
影响因子：
--
作者：
Dai, Chongshan;Li, Jichang;Li, Jian
通讯作者：
Li, Jian
粘菌素对小鼠感觉神经传导速度和F波的影响
影响因子：
3.1
作者：
Dai, Chongshan;Tang, Shusheng;Xiao, Xilong
通讯作者：
Xiao, Xilong
影响因子：
15.1
作者：
Falagas, Matthew E.;Kasiakou, Sofia K.
通讯作者：
Kasiakou, Sofia K.